A Study to Evaluate the Safety and Effectiveness of Crinecerfont in Adults with Classic Congenital Adrenal Hyperplasia

Overview

About this study

The purpose of this study is to evaluate the effectiveness of NBI-74788 (100 mg twice daily [bid]), compared with placebo, in reducing daily glucocorticoid dosage while maintaining adrenal androgen control, in reducing adrenal steroid levels following an initial 4-week treatment period, on clinical endpoints associated with supraphysiologic (greater than normal) glucocorticoid dosing, to evaluate plasma concentrations of NBI-74788 and metabolites, and to assess the safety and tolerability of NBI-74788.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Subjects must provide written informed consent.
  • Be a female or male, at least 18 years of age.
  • Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH based on standard medically accepted criteria such as elevated 17-OHP level, confirmed CYP21A2 genotype, positive newborn screening with confirmatory second-tier testing, or cosyntropin stimulation.
  • Be on a stable, supraphysiologic glucocorticoid dose regimen (defined as > 14 mg/m^2/day in hydrocortisone dose equivalents) that has been stable for at least 1 month prior to screening, is intended for chronic use, and consists of 1 or more of the following glucocorticoids: hydrocortisone (except sustained release), prednisone, prednisolone, methylprednisolone, or dexamethasone. Subjects who are on dexamethasone alone must be receiving ≥ 0.5 mg/day.
  • If treated with fludrocortisone, dose should be stable for at least 1 month prior to screening with an upright plasma renin activity (PRA) during screening within the normal range on the subject’s usual sodium intake. If PRA is not within the normal range, the subject must have systolic blood pressure > 100 mmHg, without orthostatic hypotension, and with serum sodium and potassium in the normal range.
  • Female subjects of childbearing potential with fertile male partners must agree to use contraception consistently from screening until the final study visit or 30 days after the last dose of study drug, whichever is longer. A female who is not of childbearing potential must meet one of the following:
    • Postmenopausal, defined as no menses for 12 months without an alternative medical cause and confirmed by elevated follicle-stimulating hormone (FSH) consistent with a postmenopausal range;
    • Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy; or
    • bilateral oophorectomy.
  • Acceptable methods of contraception include the following:
    • Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film);
    • Diaphragm with spermicide (with or without condom);
    • Cervical cap with spermicide (with or without condom);
    • Vaginal sponge impregnated with spermicide used with condom.
    • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS);
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal, at least 2 months prior to screening;
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal, at least 2 months prior to screening;
    • Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted, at least 2 months prior to screening;
    • Bilateral tubal ligation;
    • Total abstinence from sexual intercourse (periodic abstinence is not acceptable);
    • Sexual partner(s) who had been vasectomized at least 3 months prior to screening or medically confirmed successful procedure. 
  • Male subjects must agree to use contraception consistently from screening until 90 days after the last dose of study drug. The acceptable method of contraception for male subjects is condom with spermicide (cream, spray, foam, gel, suppository, or polymer film).

Exclusion Criteria:

  • Have a known or suspected diagnosis of any of the other forms of classic CAH including 11-β-hydroxylase deficiency, 17-α-hydroxylase deficiency, 3-β-hydroxysteroid dehydrogenase deficiency, P450 side-chain cleavage deficiency, or P450 oxidoreductase deficiency.
  • Have a history of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic therapy with oral, inhaled, or intranasal glucocorticoids.
  • Evidence of glucocorticoid overtreatment during screening, as evidenced by preglucocorticoid morning 17-OHP less than the ULN, post-glucocorticoid morning 17-OHP less than the lower limit of normal, or morning androstenedione level less than the lower limit of normal, based on normal ranges for age and sex.
  • At increased risk of developing adrenal crisis in the Investigator’s opinion, based on, for example, repeated history of adrenal crisis in the past, prior history of adrenal crisis precipitated by reducing glucocorticoid dose, recent episode(s), etc.
  • Have a clinically significant medical condition or chronic disease (including history of neurological, hepatic, renal, cardiovascular, gastrointestinal, significant malabsorption, hematologic, pulmonary, psychiatric, or endocrine disease [excluding CAH]) that in the opinion of the investigator would preclude the subject from participating in and completing the study or that could confound interpretation of study outcome.
  • History of malignancy, unless successfully treated with curative intent and considered to be cured.
  • Have a known history of clinically concerning cardiac arrhythmia (including long QT syndrome) or prolongation of screening (pre-treatment) QT interval corrected for heart rate using Fridericia’s correction (QTcF) of > 450 msec (males) or > 470 msec (females).
  • Known sensitivity (i.e., hypersensitivity) or allergy to any corticotropin-releasing hormone (CRH) receptor antagonist.
  • Have evidence of chronic renal or liver disease based on any of these screening laboratory test abnormalities:
    • Serum creatinine > 1.5 × ULN;
    • Aspartate aminotransferase (AST) > 3 × ULN;
    • Alanine aminotransferase (ALT) > 3 × ULN;
    • Total bilirubin > 1.5 × ULN unless due to a documented diagnosis of Gilbert's syndrome.
  • Have any of the following hematologic abnormalities at screening:
    • Hemoglobin 1.3, unless the subject is on anticoagulant treatment that affects INR;
    • White blood cell (WBC) count < 3.0 × 10^3 /mm^3;
    • Platelet count < 100,000/mm^3;
    • Absolute neutrophil count < 1.0 × 103 /mm^3.
  • Have any of the following abnormal coagulation abnormalities at screening:
    • Activated partial thromboplastin time (aPTT) that exceeds ULN values by more than 5 seconds;
    • Prothrombin time (PT) expressed as international normalized ratio (INR) > 1.3, unless the subject is on anticoagulant treatment that affects INR.
  • Used any active investigational drug within 30 days or 5 half-lives (whichever is longer) before screening, or plans to use an investigational drug (other than the study drug) during the study.
  • Are using any excluded concomitant medication and cannot discontinue use of these medications for the duration of the study.
  • Has current substance dependence or substance or alcohol abuse (drugs including controlled substance or non-prescribed use of prescription drugs; nicotine and caffeine dependence are not exclusionary).
  • Have a significant risk of suicidal or violent behavior. Subjects with any suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and intent) in the past 6 months before screening or any history of suicidal behavior within the past year based on the Columbia-Suicide Severity Rating Scale (C-SSRS) should be excluded.
  • Have had a blood loss ≥ 550 mL or donated blood or blood products within 8 weeks before Day 1 (baseline).
  • Females who are pregnant or lactating.
  • In the Investigator’s opinion, the subject is not capable of adhering to the protocol requirements.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Irina Bancos, M.D.

Open for enrollment

Contact information:

Melinda Thomas B.S.

Thomas.Melinda@mayo.edu

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

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CLS-20490914

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